A mechanistic model for individualised treatment of anxiety disorders based on predictive neural biomarkers

Abstract

Increased amygdala responsiveness is the hallmark of fear and a characteristic across patients with anxiety disorders. The amygdala is embedded in a complex regulatory circuit. Multiple different mechanisms may elevate amygdala responsiveness and lead to the occurrence of an anxiety disorder. While top-down control by the prefrontal cortex (PFC) downregulates amygdala responses, the locus coeruleus (LC) drives up amygdala activation via noradrenergic projections. This indicates that the same fearful phenotype may result from different neural mechanisms. We propose a mechanistic model that defines three different neural biomarkers causing amygdala hyper-responsiveness in patients with anxiety disorders: (a) inherent amygdala hypersensitivity, (b) low prefrontal control and (c) high LC drive. First-line treatment for anxiety disorders is exposure-based cognitive behavioural therapy, which strengthens PFC recruitment during emotion regulation and thus targets low-prefrontal control. A treatment response rate around 50% (Loerinc et al., 2015, Clinical Psychological Reviews, 42, 72–82) might indicate heterogeneity of underlying neurobiological mechanisms among patients, presumably leading to high variation in treatment benefit. Transforming insights from cognitive neuroscience into applicable clinical heuristics to categorise patients based on their underlying biomarker may support individualised treatment selection in psychiatry. We review literature on the three anxiety-related mechanisms and present a mechanistic model that may serve as a rational for pathology-based diagnostic and biomarker-guided treatment selection in psychiatry.

Activation of Functional Brain Networks in Children With Psychogenic Non-epileptic Seizures

“…Phasic activation of the LC in response to stress results in global activation of the whole brain, shut-down of the prefrontal cortex, and a strengthening of automatic subcortical processes (Arnsten, 2015;Atzori et al, 2016). In adult studies, approximately 70-83% of patients report multiple panic-like symptoms during PNES (Vein et al, 1994;Hendrickson et al, 2014), which is associated with high LC drive and noradrenalin release, as well as enhanced amygdala responsiveness and low prefrontal control (Brehl et al, 2020). It is possible that stress-related surges of norepinephrine contribute to a temporary disruption in horizontal and vertical network function in children with PNES (Barzegaran et al, 2016;Kozlowska et al, 2018a) or to functional shift in organization where functional connectivity patterns that support automatic processes of survival value are prioritized (Arnsten, 2015;Szaflarski and LaFrance, 2018).…”

Restricted visual scanpaths during emotion recognition in childhood social anxiety disorder

“…Brain imaging studies have shown amygdala hyperreactivity to threat in SAD (Frick et al, 2013;Gentili et al, 2016). Increased LC-NE activity could lead to amygdala hyperreactivity through downregulation of inhibitory GABA neurons in the amygdala (Brehl et al, 2020). In light of previous studies, it could therefore be expected that SAD would be associated with enhanced pupil dilation to emotional faces.…”

Anxiolytic effects of chronic intranasal oxytocin on neural responses to threat are dose-frequency dependent

“…With respect to neurofunctional alterations in the dlPFC both increased as well as decreased activity has been reported in anxiety disorder. Attenuated dlPFC activity during cognitive emotion regulation is interpreted to underlie deficient regulatory control, while increased activity during emotion perception may reflect enhanced attentional and salience processing of potentially threatening stimuli (Brehl et al, 2020;Bruce et al, 2013;Morgan et al, 1993;Quirk et al, 2003). Moreover, the anterior insula and lateral PFC have been suggested to play a role in several general domains associated with anxious arousal, including tonic alertness and arousal as well as threat specific domains such as expectation of predictable threat and threat vigilance (Ironside et al, 2016;Wheelock et al, 2014).…”

“…Anxiety engages a broad network of subcortical and cortical systems, with amygdala, insula and prefrontal (PFC) regions being among the most consistently identified (Bishop et al, 2004;Calder et al, 2011;Calhoon & Tye, 2015;Etkin & Wager, 2007;Larson et al, 2005;Robinson et al, 2019;Tovote et al, 2015;Xu et al, 2021;Zhao et al, 2019) in a network mediating arousal, alertness and vigilance (Sadaghiani & D'Esposito, 2015). Neuroimaging meta-analyses and treatment evaluation studies have demonstrated that patients with anxiety disorders exhibit exaggerated reactivity in this network in response to threatsignaling and negative emotional stimuli (Chavanne & Robinson, 2020;Etkin & Wager, 2007;Xu et al, 2021), while some functional dysregulations in the amygdala-insula-prefrontal circuitry normalize with successful intervention (Brehl et al, 2020;De Cagna et al, 2019;Goossens et al, 2007;S. M. Gorka et al, 2019;Ipser et al, 2015;Spengler et al, 2017).…”